Ureides containing a quaternary carbon atom



Patented Nov. 1, 1938 PATENT OFFICE 3,135.08 UBEIDIS OONIAINING A GUAM!CAI-ION ATOH lower, St. Louis. Ma, and Noll, State College, Pa., rodtChemical Works.

ration of Missouri wslmstm collegel'ashaglst Clarence!- MIDW-8t.llouis,llo.,aeorpo- No mm. Application February is, me.

Serial dclaima (cam-ml This invention relates to ureides. and withregard to certain more specific features, to ureides containing in theirstructure a quaternary carbon atom.

This application is input a continuation of the application of thepresent inventors Whitmore and Homeyer, Serial No. 666,512, filed April17, now Patent No. 2,034,850, dated March 24,

Among the several objects of the invention may be noted the provision,as new compositions of manger, of ureides corresponding to the type formwhere Rl is hydrogen or a halogen, R: is hydrogen or a hydrocarbonradical, and It: is a hydrocarbon radical containing a quaternary carbonatom; the provision of ureides corresponding to the type formula setforth which are valuable for their therapeutic eflects; and theprovision of processes for manufacturing ureides of the type 25 setforth which produce products of a high degree of purity. and which maybe carried out upon The present invention is particularly concerned withthe production of ureides including a substituent group on thealpha-carbon atom of the ureide nucleus, said substituent group havingsuch a quaternary carbon atom in its structure. So far as the presentinvention is concerned, the values or compositions of the othersubstituents on the alpha-carbon atom of the ureide nucleus, or, forthat matter, the substituents on the nitrogen atoms of the ureidenucleus, are of little moment. These other substituents may be varied atwill, within the skill of an organic chemist, and hence ureides sosubstituted are to be considered as included within the scope of thepresent invention.

A general method of manufacturing ureides corresponding to the typeformula set forth comprises condensing urea with an acid correspondingin turn to the type formula:

(R1, R2. and Rs having the same meaning as set forth hereinbefore)according to the reaction:

readily obtainable materials and with a of complicated procedures. otherobjects will be iri hrrt obvious and in-part pointed out hereina r Theinvention accordingly comprises the elements and combinations ofelements, and leatures of composition which will be exemplified in theproducts hereinafter described, and the scope of the application ofwhich will be indicated in 4 5 the following claims. 1

It has recently been determined that certain organic products includingas a constituent thereof, a carbon atom, that is, a carbon atom linkedto four other carbon atoms. have valuable proper- 50 ties, particularlyin the field of hypnoti sedatives, soporiflcs. analgesics, bactericides,and the like. The ureides containing a quaternary carbonatolnappeartohaveparticularutilityinthe held of sedatives and soporlfics, andpossibly also 55 hypnotics.

B- It is not infrequently more convenient to start with an acyl halidein place of the acid. the reaction then being:

Be or being a halogen atom, usually chlorine or bromine.)

set forth hereinafter, this In the examples basic process is carriedthrough with a number m 1 Term butvl oeetvi area m is the simplestsubstance comprehended within the stated definitions of the typeformula. Its formula is as follows:

( CH: sC-CHs-CO-NH-CO-NH:

(CH3) Mlle-COG] +NHaCO-NHs- (CH1) MHz-CO-NH-CO-N'Hs-i-HCI Tertiary butylacetyl chloride may be obtained in pure form by following the procedureoutlined in the aforesaid Patent No. 2,034,850. Details of the procedurefollow:

25.3 grams of tertiary butyl acetyl chloridearemixedwith253gramsofureainafiask. andtheflaskisheatedfortwohoursonasteam bath. Only a slight odor then remains. The solid product in theflack is then washed with 200 cc. of a 5% solution of sodium bicarbonateand cc. of water, and thereafter air-dried on a Buchner funnel. Afterfurther drying in a desiccator, the solid product is recrystallizedthree times from ethyl acetate. The final recrystallized product, in theform of white crystals, has a melting point of to 172 0.

Exams: 2 ZJ-dimethylproprl-methvl-dcetvl area This substance has thefollowing structural formula:

g: c co 1m 00 mm It: is now exhibited as methyl, while B; is 2.2--dimethylprcpyl. This substance may be made by reacting2,2-dimethylpropyl-methyl-acetyl chloride with urea, the reaction beinganalogous to that set forth in Example 1. Since the preparation of2,2-dimethylpropyl methyl acetyl chloride is not elsewhere described, itwill be given in detail hereinafter.

Tertiary butyl chloride, which is commercially obtainable, is used asthe startingmaterial. Ibis is first converted into the correspondingGrignard compound, tertiary butyl magnesium chloride, by well-knownmethods. The Grig'nard compound is then reacted with allyl bromide,which is likewise commercially obtainable, according to the reaction:

(CH4) sC-MICH-MW (CH1) sc-cm-cn=cm+ngcmr the product being the olefine.4.4-dimethylpentene-l. This olefine is then hydrowithhydrogenbromideinthepruanceofdiphenylamine according to thereaction:

ThisbromideiatheninturnreactedwithmagnesiumtoobtainitsGrignard,andtheGrignar-dcompoimdthusobtainedisreactedwithcarbondioxide,accordingtothereaction:

for example. by a well-known reaction. Details of this preparationfollow.

Details for the preparation of the Grignard compound of tertiary butylchloride are not given, as this is a customary procedure in organicsyntheses.

Starting, then, with an ether solution of the Grignard compound,tertiary butyl magnesium chloride, the following procedure may beutilized:

605 grams of allyl bromide and 600 cc. of dry ethyl other are placed ina three-neck flask q pped with a mechanical stirrer, a separatoryfunnel, and a thermometer. The mixture is cooled by ice and salt, andtertiary butyl magnesium chloride solution, which has been carefullyfiltered, is added at such a rate that the temperature remains nearzero. A total of 2400 cc. of the Grignard reagent,'whleh has aconcentration of 2.2 mole per liter, is added during twenty-four hours.After warming to 30 C. for an hour, with stirring, the liquid issiphoned oil into a funnel containing crushed ice. However, themagnesium halide ether complex forms a solid cake within the flask, sothis is loosened with a stirring rod, slurried with ether, and added tothe contents of the funnel. The ether layer is then separated from thewater and washed with an ammoniacal solution of ammonium sulphate. Thecombined water layer and washings are steam distilled 'and the etherlayer thus obtained is added to the main ether portion. The combinedother portions are then dried over calcium chloride, and fractionated,the portion boiling between 68 C. and 71.2 0., at atmospheric pressure,being collected as the product, 4,4-dimethylpentene-1. The amountcollected is4l9 grams, or a yield of 86% based upon the allyl bromideused. The product is a colorless liquid, having an index of refractionbetween 1.8902 and 1.3920.

The above olefine, before proceeding further, may be purified in thefollowing manner: First. the olefine is converted into its dibromidewith bromine in an ether or chloroform solution at 5 C. The dibromide isthen fractionated at a reduced pressure, and the fraction from 7'1 C. to78 C. (at 9 mm. pressure) is collected. lhe olefine is then regeneratedby allowing the dibromide to fiow drop-wise into a refluxing arrangementincluding a stirred suspension of nine dust in ethyl alcohol, at boilingtemperature.Afterthiatheolefineisremovedbyusualmethodsfromthealcoholicsoiution.Theyieldis greater-thanw'fi. 'lhisprocedureisparticularly valuable forremoving diallyl and other impuritimfromthecrudeolefine. Thepureoiefinehasaboillng pointofl2.350.at'l00mm.pressure, an index of refraction of1.3911, and a density of 0.6827.

However, theolefineneed notnecesaarilybe purified at this tale.

200 grams of 4,4-dimethylpentene-1. Preparedasaboveareweighedintoaone-litenthrw denser, a thermometer, amercury-sealed stirrer, and a 50 cc. pipette delivery tube. 10.2 gramsof diphenylamine are next added to the olefine, followedbyafurther10.2gramsofdiphenylamine in200gramscf'f5% aceticacid. 'I'hemixture isthen cooled to -2 c. in a salt-ice bath. n bromide. prepared bydroppingliquid bromine on naphthalene and freed of bromine by passage overredphosphorotmisthenpassed into the oleiine for three hours. after whichthe chloride. The water layer is steam distilled, and

the small additional oily bromide layer is added to the main bromideseparated. The bromide is then fractionated, two distinct products beingcollected. The lower boiling point fraction is the desired 4,4 dimethyl2 -bromo pentane, which boils at 74.0 to 75.0 0., under 65 to 6''! mm.

pressure, and has an index oi retraction oi 1.4460.

to 1.4462. The higher boiling point fraction is4,4-dimethyl-1-bromopentane, which is not wanted tor present purposes.

Next, 9 grams (0.3 mole) of magnesium turnings is weighed into a 500 cc.three-necked flask fltted with a mercury-sealed stirrer, a droppingfunnel. and a reflux condenser. The top of the dropping tunnel isconnected to the reflux condenser and to a Gilman sulphuric acid trap. Afew crystals of iodine are dissolved in 10 cc. 0! dry ethyl ether, andthe solution is added to the magnesium in the flask. 5 grams of4,4-dimethyl-2-bromopentane, prepared as above, is now added to thecontents of the flask and the flask is warmed with matches. The reactioncommences within 5. minutes after the addition of the bromide. 25 cc. ofdry ethyl ether is next added to the contents oi the flask, andthereafter, over a period oi 2% hours, a solution of 55 grams01.4,4-di1nethyl-2-bromopentane in 100 cc. of dry ethyl ether, is slowlyadded to the contents of the flask.

The resulting Grlgnard compound is cooled in an ice bath, and thereaftersolid carbon dioxide is added to saturation. The solution is thendecomposed by pouring it on ice. After making the solution acid with 25%sulphuric acid, the ether layer is allowed to separate and the waterlayer is steam-distilled, the ether fraction from the steam-distillatebeing added to the orieinal ether cur-ca. 'coocim (1) 0 211:0(OHshG-OHs-CH: OOOGsHI One-OH m s\c/OOOH 4, (OKlhO OHr-OBs OKs-O (8)cn-ooonuoci.

( ui -133F030 cm-c (GHshC-CHs-OHI 0 8-0 0 OI+NH 108.5 0., under 14 mm.pressure, and has an index 01 refraction of 1.422! to 1.4230, and adensity oi 0.9000.

21.1 grams of the acid are weighed into a 200 cc., three-necked flaskfltted with a reflux condenser and a dropping tunnel. 40 grams oithionyl chloride (SOCla) are then added in two hours, and the mixture isthen heated on a steam bath for 5% hours, after which it isfractionated. The product, 2,2-dimethylpropyl-methyl-acetyl chloride, isa colorless liquid boiling at 102 to 103 0., under 117 to 118 mm.pressure, and has an index of refraction of 1.4307 to 1.4310, and adensity of 0.9454. p

4.8 grams of this acetyl chloride are mixed with 3 grams of urea in a 50cc. Erlenmeyer flask, and the mixture is heated on a steam bath forabout 3 hours, then allowed to stand 0 night, and then returned to thesteam bath for a further 2 hours. The product is washed with '10 cc. of5% sodium bicarbonate solution, filtered, and washed with water, andthereafter recrystallized from ethyl alcohol and dried in a vacuumdesiccator at to mm. pressure.

The product, 2,2-dimethylpropyl-methyl-acetyl urea, is a whitecrystalline solid melting at 177 to 178 0.

Exam: 3

3,3-dimethyibutyl-ethyl-ocetyi area This substance has the followingstructural R: is now exhibited as ethyl, while R: is 3. 3- dimethybutyl.This substance may be made by reacting 3,3-dimethylbutyi-ethyl-acetylchloride with urea, the reaction being analogous to that set forth inExample 1.

3,3-dimethylbutyl-ethyl-acetyl chloride may be made by acylization oithe corresponding acid. which acid may in turn be made from the malonicester, 2,2-dimethyl-5,5-dicarbethoxyheptane (the preparation of which isdescribed in detail in the copendlng application of the presentapplicants Whitmore and N011, together with David M. Jones, Serial No.83,212, tiled February 10, 1938) by well-known processes, according tothe following series oi reactions:

GHr-CH: coon c 20sHsOH coon cut-ca.

on-ooos tomcat-01! OKs-CHI (enemas-ca.

(om-carom Reaction (1) isaccomplished, i'or example, by refluxing theesterwith potassium hydroxide, and reaction (2) proceeds merely with theaid of heat. Reactions (3) and (4) are analogous to those given indetail in connection with Example 2 oi this application, and hence willnot be repeated in detail herein.

The product ureide is a white crystalline solid.

V'UI-dicarbethoxynonane Exams: 4

4,4-dimethgipentyl-ethul-aeetul area This substance has the followingstructural formula:

R: is again exhibited as ethyl. while R1 is 4,4- dimethylpentyl. Thissubstance may be made by reacting 4,4-dimethylpentyl-ethyl-acetylchloride with urea, the reaction being analogous to that set forth inExample 1.

4,4dimethylpentyl-ethyl-acetyl chloride may be made from the malonicester, 2,2-dimethyl- 6,6-dicarbethoxyoctane (the preparation of which isdescribed in detail in said copending application serial No. 63,212)according to reactions analogous to those set forth in connec tion withExample 3 herein.

The acid obtained in the course of this synthesis,4,4-d1methylpentyl-ethyl-acetic acid, is a colorless liquid boiling. at103-105" 0., under 1 to 2 mm. pressure, and has an index of refractionof 1.4320 to 1.4328. 7

The product ureide is a white crystalline solid melting at 118 to 119 C.

Exunms 5 4,4-dimethylherul-cthpl-acetpl area This substance has thefollowing structural formula:

R2 is again exhibited as ethyl, while B: is a new form of quaternarycarbon-containing alkyl (the quaternary atom having two methyl groupsand one ethyl group attached, in place of three methyl groups asheretofore). This substance may be prepared by reacting4,4-dimethylhexylethyl-acetyl chloride with urea, the reaction beinganalogous to that set forth in Example 1.

1,4-dimethylhexyl-ethyl-acetyl chloride may be made from the malonicester, 3,3-dimethyl- (the preparation of which is described in detail inthe said copending application Serial No. 63,212) according to reactionsanalogous to those set forth in connection with Example 3 herein.

The product ureide is a white crystalline solid.

Exusru 6 IA-dimethfllpenWHMwl-acetyl area This substance has thefollowing structural formula:

R: is now exhibited as phenyl (an aryl) while B: is 4, t-dimethylpentyi,as in Example 4. This substance may be made by reacting 4,i-dimethylpentyl-phenyl-acetyl chloride with urea, the reaction beinganalogous to that set forth in Example 1.

4,4 dimethylpentyl phenyl acetyl chloride may be made from the malonlcester, 1, l-dicarbethon-l-phenyl-S, S-dimethylhexane (the preparation ofwhich is described in detail in the said oopending application SerialNo. 83,212) accord- Exams 7 AIpha-bromo' mm tum acetwl area Thissubstance has the following structural formula: 1

R1 is exhibited as bromine. R: as hydrogen, and R: as tertiary butyl.This substance may be made by reacting alpha-bromo tertiary butyl acetylbromide (described and claimed in the copending application of thepresent applicants Whitmore and Homeyer, Serial No. 666,512, flied April1'1, 1933) with urea, the reaction being analogous to that set forth inExample 1.

The product ureide is a white crystalline solid. having a melting pointof about 138.5 C.

An alternative method of making this ureide is to react urea withalpha-bromo tertiary butyl acetic acid, under suitable conditions. Sincealpha-bromo tertiary butyl acetic acid is not elsewhere described, itspreparation is given in detail hereinafter:

23 grams of tertiary butyl acetic acid (prepared as set forth inWhitmore et al. Patent No. 2,004,- 066, dated June 4, 1035) and 18 cc.of dry bromine (a 10% excess) are placed in a 200 cc. flask fitted witha reflux condenser arranged for collecting the evolved hydrogen bromidein water. One cc. of phosphorus trichioride is added and the mixture iswarmed at 60 to 70 C. for three hours and then at 100 C. for an hour.Hydrogen bromide is evolved and all of the bromine pressure.

Exams: 8

2,2 dimcthplml methyt-alpha-bromoaoetpl area This substance has thefollowing structural formuia:

ItisthesameasthesubstanceofExample2,exceptinthatltiisbromineinsteadofbydrogen.It is made by the same method as Example 3, except that azfi-dimethylpropyl-methyl-alphal halide is used in place of the 2,2-dimethyl-propyl-methyl-acetyl chloride of Example 2.

zfl-dimethylpropyl-methylealpha-lromoaeetyl halides may be made from2,2-dimethylpropyimethyl-acetyl chloride in the following manner: 134.6grams of the latter substance are placed in a 500 cc., three-neckedflask fitted with a reflux condenser and a dropping funnel. 20 drops ofphosphorus tribromide are then added to the flask, and thereafter, overa period of 1% hours, 132 grams of liquid bromine are added. Thereaction mixture is then heated on a steam bath for 8% hours, and thenfractionated. The bromoecetyl halide obtained, probably the chloride, isa, colorless liquid boiling st 107.5 to 110.0 C. \mderllimmpressuresndhsssnindexo! retraction of 1.5050 to 1.5058.

Theureideproductobteinedisewhitecrystolline solid melt-in: at 138.7 to139.7 C.

ltisobviousthstotheralphs-d' 20 departing ill-om theseope oftheinventiomitis ,intendedthetelimsttercontainedintheabove GERI'TFICATEor CORRECTION.

1 retent lo; 2,155,06L.

description shill be interpreted as illustrative and not in a limitingsense.

We claim: 1. A ureide corresponding to the type formula:

\ m-O-c o-rm-o 0-4111,

where R: is one of the group consisting of hydrogen snd the halogens, Reis one of the group conaistinz of hydrogen. the lower alkyis, andphenyl, andRaisanelkylcontsininzoqmternsrycarhon atom in its structure.

2. 2,2-dimethylnronyi-meth7l-eoetyl urea. 3. Alpha-memo tertiary hutylecetyi urea. 4. 2, 2-dimethylpropyl methyl elpha-bromoacetyl urea.

RANK 0. WEIIMIORIL AUGUST H. HOMEYER. CLARENCE 1. ROLL.

November 1,1938

FRANK G. HHI'BIORE, ET AI It is hereby certified that error appears inthe printed specification of the shove mnnbered patent requiringcorrection as follows Page 2, first co1umn,"1ihe 22, for "flack! readflask; and-second column, line hi, for the immoral "1,8902" read 1.3902;and that the said letters Patent should be reed Iiththis correctiontherein that the same ma'y'eonform .to ..the record o.f the case thePatent Office.

' Signed and eealedthis 2b,th day of i. D. 1939.

Henry Vsn Aredsle Acting Gommissioner of Patents.

ecetyl halide obtained, probably the chloride, is a, colorless liquidboiling st 107.5 to 110.0 C. \mder llimmpressuresndhsssnindexo!retraction of 1.5050 to 1.5058.

Theureideproductobteinedisewhitecrystolline solid melt-in: at 138.7 to139.7 C.

ltisobviousthstotheralphs-d' 20 departing ill-om theseope oftheinventiomitis ,intendedthetelimsttercontainedintheabove GERI'TFICATEor CORRECTION.

1 retent lo; 2,155,06L.

description shill be interpreted as illustrative and not in a limitingsense.

We claim: 1. A ureide corresponding to the type formula:

\ m-O-c o-rm-o 0-4111,

where R: is one of the group consisting of hydrogen snd the halogens, Reis one of the group conaistinz of hydrogen. the lower alkyis, andphenyl, andRaisanelkylcontsininzoqmternsrycarhon atom in its structure.

2. 2,2-dimethylnronyi-meth7l-eoetyl urea. 3. Alpha-memo tertiary hutylecetyi urea. 4. 2, 2-dimethylpropyl methyl elpha-bromoacetyl urea.

RANK 0. WEIIMIORIL AUGUST H. HOMEYER. CLARENCE 1. ROLL.

November 1,1938

FRANK G. HHI'BIORE, ET AI It is hereby certified that error appears inthe printed specification of the shove mnnbered patent requiringcorrection as follows Page 2, first co1umn,"1ihe 22, for "flack! readflask; and-second column, line hi, for the immoral "1,8902" read 1.3902;and that the said letters Patent should be reed Iiththis correctiontherein that the same ma'y'eonform .to ..the record o.f the case thePatent Office.

' Signed and eealedthis 2b,th day of i. D. 1939.

Henry Vsn Aredsle Acting Gommissioner of Patents.

